Abstract
BackgroundThere are seven insulin-like growth factor binding proteins (IGFBPs) that bind insulin-like growth factors (IGFs). IGFBP like protein1 (IGFBPL1) is a new member of this family. The function and mechanism of IGFBPL1 in esophageal cancer remains to be elucidated.MethodsEight esophageal cancer cell lines, 114 cases of esophageal dysplasia, and 501 cases of primary esophageal cancer samples were examined in this study. Methylation-specific polymerase chain reaction (MSP), immunohistochemistry, Western blot, flow cytometry, RNA interference assay, and xenograft mouse models were employed.ResultsThe expression of IGFBPL1was lost and complete methylation was found in KYSE150 and KYSE410 cells. Reduced expression and partial methylation of IGFBPL1 was found in Bic1, KYSE140, KYSE450, KYSE520, and COLO680N cells. High expression and unmethylation was detected in KYSE510 cells. Restoration of IGFBPL1 expression was found in KYSE150 and KYSE410 cells and the expression of IGFBPL1 was increased in Bic1, KYSE140, KYSE450, KYSE520, and COLO680N cells, after 5-AZA-2′-deoxycytidine treatment. IGFBPL1 was methylated in 47.3% (53/114) of esophageal dysplasia and 49.1% (246/501) of human primary esophageal squamous cell carcinoma (ESCC). Methylation of IGFBPL1 was significantly associated with TNM stage (p = 0.012), and tumor size (p = 0.009). IGFBPL1 inhibited esophageal cancer cell clonal formation and proliferation and induced cell apoptosis and G1/S phase arrest. Further study found that IGFBPL1 is involved in PI3K-AKT signaling and IGFBPL1 suppressed human ESCC xenografts growth in mice.ConclusionIGFBPL1 suppresses esophageal cancer cell growth by inhibiting PI3K-AKT signaling in vitro and in vivo. IGFBPL1 is a novel tumor suppressor in human esophageal cancer.
Highlights
Esophageal cancer is the sixth most common cause of cancer related death worldwide [1]
The expression of IGFBP like protein1 (IGFBPL1) is downregulated by promoter region methylation in esophageal cancer cell lines IGFBPL1 expression was detected by semi-quantitative RT-PCR in esophageal cancer cell lines
To further reveal that the expression of IGFBPL1 is regulated by promoter methylation, cells were treated with 5-AZA
Summary
Esophageal cancer is the sixth most common cause of cancer related death worldwide [1]. Esophageal cancer mainly consists of two cell types, esophageal squamous cell carcinoma (ESCC), and adenocarcinoma (EAC). ESCC is the predominant histological type and accounts for 90% of the cases of esophageal carcinoma worldwide [4]. Inactivating mutations of NOTCH1 were identified in 21% of ESCCs but not in EACs. Notably, NOTCH1 mutations were more frequent in North American ESCCs (11 of 53) compared to ESCCs from China (1 of 48 cases) according to Sanger sequencing validation [6]. Using whole genomic sequencing of ESCC samples from China, Song et al found that somatic aberrations are mainly involved in the Notch, Wnt, and. IGFBP like protein (IGFBPL1) is a new member of this family. The function and mechanism of IGFBPL1 in esophageal cancer remains to be elucidated
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